Editors' ChoiceCancer

Stromal-Induced Survival

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Science Signaling  16 Jul 2013:
Vol. 6, Issue 284, pp. ec160
DOI: 10.1126/scisignal.2004509

The p53-related transcription factor p63 (also called TAp63) regulates embryonic epithelial development. The isoform lacking the p53-like transactivation domain (ΔNp63) is the major p63 isoform found in squamous cell carcinoma (SCC). Using a mouse model, Ramsey et al. found that SCC cells in vivo are “ΔNp63-addicted” and that prosurvival signaling is induced by the stroma. In mice expressing a tissue-specific conditional knockout allele of p63, carcinogen-induced SCC tumors in which p63 was knocked down had increased abundance of cleaved caspase-3 (a marker of apoptosis), decreased abundance of the proliferation marker Ki67, and decreased tumor volume. Global gene expression profiling and pathway analysis identified gene targets of p63 that encode proteins involved in integrin signaling, the RAS to MAPK (mitogen-activated protein kinase) signaling module, and the FGF (fibroblast growth factor) signaling pathway. The abundance of ΔNp63 transcripts correlated with that of FGF receptor 2 (FGFR2) transcripts in human SCC tissue, and knockdown of either total p63 or FGFR2 reduced anchorage-independent growth and colony formation by human SCC cells. Colony formation was restored by overexpression of wild-type but not a DNA-binding-deficient ΔNp63. Compared with SCC cell lines, human and mouse SCC tumors had increased transcript abundance of p63, FGFR2, and FGF1, FGF7, and FGF10, which are transcripts for FGFR2 ligands. In endogenous mouse tumor tissue, the abundance of FGF7 was high in the dense stroma surrounding SCC tumors but barely detectable in the tumor, whereas the opposite was observed for FGFR2 and p63. Pharmacological inhibition of FGFR2 signaling arrested the progression of endogenous SCC tumors in the mice and increased their survival. Together, the findings indicate that targeting ΔNp63 or paracrine-activated FGFR2 signaling may be a new treatment strategy for SCC.

M. R. Ramsey, C. Wilson, B. Ory, S. M. Rothenberg, W. Faquin, A. A. Mills, L. W. Ellisen, FGFR2 signaling underlies p63 oncogenic function in squamous cell carcinoma. J. Clin. Invest. doi:10.1172/JCI68899 (2013). [Online Journal]